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Oyster peptide (OP) and Pfaffia glomerata extract (PGE) were used as raw materials. The optimal formulation of the pressed candy (PC) was optimized by one‐way experiment and D‐optimal mixture experiment design, and animal experiment was used to evaluate the effect of PC on male sexual dysfunction. The results showed that PC intervention significantly improved the sexual behavior of male mice with sexual dysfunction, including a significant shortening of the mount latency (ML) and intromission latency, and a significant increase in the mount frequency (MF) and intromission frequency (IF). At the same time, the concentrations of serum testosterone (T) and luteinizing hormone (LH) in mice were restored, and the erectile parameters and pathological changes of penile tissue were improved. Further studies found that PC intervention increased the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH‐Px) and reduced the content of malondialdehyde (MDA) in testicular tissue. In addition, PC intervention improved testicular tissue morphology. In conclusion, the obtained PC has good taste quality, and the relevant quality indicators are qualified. It has a good ameliorative effect on male sexual dysfunction and may be a potential dietary supplement. [ABSTRACT FROM AUTHOR]

This research work aimed to identify the main components that are responsible for the sedative properties of hop cones and allocate their targets. This investigation was performed through molecular docking, molecular dynamic simulations, root mean square fluctuation (RMSF) analysis, and DFT calculation techniques. The tested compounds from Humulus lupulus were compared to diazepam and paroxetine. Molecular docking showed that two-thirds of the compounds had a good affinity to gamma-aminobutyric acid (GABA), outperforming diazepam, while only three surpassed paroxetine on the SERT. Compounds 3,5-dihydroxy-4,6,6-tris(3-methylbut-2-en-1-yl)-2-(3-methylbuta noyl)cyclohexa-2,4-dien-1-one (5) and (S,E)-8-(3,7-dimethylocta-2,6-dien-1-yl)-5,7-dihydroxy-2-(4-hydroxyphenyl)chromen-4-one (15) showed stable binding and favorable energy parameters, indicating their potential for targeting GABA receptors and the SERT. This study provides a basis for future clinical research on these promising compounds. [ABSTRACT FROM AUTHOR]

Introduction: Paroxetine is an older "selective" serotonin reuptake inhibitor (SSRI) that is notable for its lack of selectivity, resulting in an anticholinergic adverse-effect profile, especially among older adults (65+). Methods: Paroxetine prescription rates and costs per state were ascertained from the Medicare Specialty Utilization and Payment Data. States' annual prescription rate, corrected per thousand Part D enrollees, outside a 95% confidence interval were considered significantly different from the average. Results: Nationally, there was a steady decrease in population-corrected paroxetine prescriptions (-34.52%) and spending (-29.55%) from 2015--2020 but a consistent, five-fold state-level difference. From 2015--2020, Kentucky (194.9, 195.3, 182.7, 165.1, 143.3, 132.5) showed significantly higher prescriptions rates relative to the national average, and Hawaii (42.1, 37.9, 34.3, 31.7, 27.7, 26.6) showed significantly lower prescription rates. North Dakota was often a frequently elevated prescriber of paroxetine (2016: 170.7, 2018: 143.3), relative to the average. Neuropsychiatry and geriatric medicine frequently prescribed the most paroxetine, relative to the number of providers in that specialty, from 2015--2020. Discussion: Despite the American Geriatrics Society's prohibition against paroxetine use in older adults and many effective treatment alternatives, paroxetine was still commonly used in the US in this population, especially in Kentucky and North Dakota and by neuropsychiatry and geriatric medicine. These findings provide information on the specialty types and states where education and policy reform would likely have the greatest impact on improving adherence to the paroxetine prescription recommendations. [ABSTRACT FROM AUTHOR]

Abstract Oyster peptide (OP) and Pfaffia glomerata extract (PGE) were used as raw materials. The optimal formulation of the pressed candy (PC) was optimized by one‐way experiment and D‐optimal mixture experiment design, and animal experiment was used to evaluate the effect of PC on male sexual dysfunction. The results showed that PC intervention significantly improved the sexual behavior of male mice with sexual dysfunction, including a significant shortening of the mount latency (ML) and intromission latency, and a significant increase in the mount frequency (MF) and intromission frequency (IF). At the same time, the concentrations of serum testosterone (T) and luteinizing hormone (LH) in mice were restored, and the erectile parameters and pathological changes of penile tissue were improved. Further studies found that PC intervention increased the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH‐Px) and reduced the content of malondialdehyde (MDA) in testicular tissue. In addition, PC intervention improved testicular tissue morphology. In conclusion, the obtained PC has good taste quality, and the relevant quality indicators are qualified. It has a good ameliorative effect on male sexual dysfunction and may be a potential dietary supplement.

Patients with major depression often suffer from excessive interpersonal sensitivity, although it is not typically measured in antidepressant clinical trials. Preliminary evidence suggests selective serotonin reuptake inhibitors have the capacity to reduce interpersonal sensitivity. This was a pooled analysis of data from 1709 patients in three randomized, double-blind, placebo-controlled trials of fluoxetine and paroxetine for acute major depressive disorder. Depressive symptoms were assessed with the Hamilton Depression Rating Scale. A factor from the Symptom Checklist was used to assess interpersonal sensitivity. Our outcome of interest was change from baseline scores at the last assessment (up to 8 or 12 weeks, depending on the trial). Both medications produced significantly greater reductions in interpersonal sensitivity relative to placebo. The effect of medication remained significant after controlling for depression improvement, which explained 18.5% of the variation in interpersonal sensitivity improvement among those treated with active medication. The effect of medication on depressive symptoms, relative to placebo, was not influenced by baseline interpersonal sensitivity. The outcome measured interpersonal sensitivity over the last week, and the results do not necessarily reflect changes in long-standing, trait-like patterns of interpersonal sensitivity. Only two medications were studied. Selective serotonin reuptake inhibitors are effective at treating interpersonal sensitivity in acutely depressed patients. This appears to be a unique drug effect that is not only the result of depression improvement. Future clinical trials might benefit from assessing interpersonal sensitivity more routinely. • Paroxetine and fluoxetine reduced interpersonal sensitivity more than placebo. • This effect could not be fully explained by concurrent depression improvement. • Baseline interpersonal sensitivity did not moderate the depression treatment effect. [ABSTRACT FROM AUTHOR]

The impacts of antidepressant pharmacotherapies on cardiovascular risk are unclear. We completed a systematic review with meta-analysis to assess the effect of paroxetine on heart rate variability (HRV) in patients with major depressive disorder (MDD). The searches were accomplished via EMBASE, MEDLINE/PubMed (using the National Library of Medicine), Cochrane Library, CINAHL, Scopus, and Web of Science databases. We included non-blind, single, or double-blind randomized control trials in patients older than 18 diagnosed with MDD. Paroxetine needs to be enforced as a chronic therapeutic medication. We included individual studies that investigated resting HRV. We documented 402 studies, only following screening and eligibility phases; only six were included (five studies in the meta-analysis). No significant change was noticed for the SDNN index: subtotal = 8.23 [CI: −2.17, 18.63], p = 0.12, I2 = 54 % (very low quality of evidence). A significant change was distinguished for the LF index: subtotal = 0.74 [CI: 0.33, 1.15], p = 0.0004, I2 = 0 % (low quality of evidence). A significant alteration was perceived for the HF index: subtotal = 0.33 [CI: 0.06, 0.6], p = 0.02, I2 = 0 % (low quality of evidence). Meta-analysis demonstrated that paroxetine could advance HRV in MDD patients. Nevertheless, our supposition is founded only on statistical analysis and the very low quality of evidence breakdown reinforces the necessity for further studies to confirm or reject this theory. • We evaluated the effects of paroxetine on heart rate variability in patients identified with major depressive disorder. • Meta-analysis specified that paroxetine improved LF and HF; • Quality of evidence for SDNN was very low and low for LF and HF. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to investigate the plasma and breastmilk concentrations for sertraline, citalopram and paroxetine for assessment of the Milk/Plasma (M/P) ratio and Absolute Infant Dose (AID), and to determine actual infant drug exposure through breastfeeding. Subsequently, informed recommendations will be formulated regarding the advisability of breastfeeding in women undergoing treatment with the three most widely used antidepressants. Methods: A pharmacokinetic study in lactating women and their infants using sertraline, citalopram or paroxetine was performed. Paired breastmilk and plasma samples and single point infant plasma samples were collected to determine antidepressant concentrations. An Area Under the Curve (AUC) based approach with the trapezoidal rule was used to calculate M/P ratios and AID for all three antidepressants by combining all measured concentrations for the same dose. Results: Thirty-seven lactating women and their infants participated in this study. 111 paired breastmilk and plasma samples and 37 single point infant plasma samples were collected. Detectable concentrations of sertraline, citalopram and paroxetine were present in all breastmilk samples. For sertraline and citalopram M/P ratio is above one, indicating higher breastmilk than plasma concentrations, however, drug exposure by breastmilk did not lead to detectable plasma drug levels in any of the 15 infants for sertraline, for nine (out of 13) infants for citalopram and for eight (out of nine) infants for paroxetine. Conclusion: Given the well-known benefits of breastfeeding, our findings support breastfeeding of infants by mothers who are taking sertraline, citalopram or paroxetine is safe. Sertraline and paroxetine are the preferred antidepressants during breastfeeding, reaching mostly undetectable infant drug levels. [ABSTRACT FROM AUTHOR]

Selective serotonin reuptake inhibitors (SSRIs) are the first-line anti-depressants. Unfortunately, about 30 % depressed patients do not effectively respond to SSRIs. It is still unclear that the gastrointestinal characteristics of responders and non-responders, and the differences. Herein, we characterized gut microbiome and metabolome of depressed rats with differential responses to Paroxetine (PX) by 16S rRNA sequencing and 1H NMR-based metabolomics, respectively. On top of this, we constructed both inter- and inner-layer networks, intuitively showing the correlations among behavioral indicators, immune factors, intestinal bacteria, and differential metabolites. Consequently, we found that depressed rats differently responded to PX, which could be divided into PX responsive (PX-R) and non-responsive (PX-N) groups. Firstly, the depressive behaviors of PX-R rats and PX-N rats significantly differed. Meanwhile, inflammatory balance was also characterized for depressed rats with different responses to PX. Overall, PX-R rats and PX-N rats exhibited differential gut microbiome and metabolome, including intestinal structures, intestinal functions, metabolic profiles, metabolites, and metabolic pathways. Metabolites that identified by metabolomics based on 1H NMR are not comprehensive enough. Taken together, our study demonstrated that gut microbiome and metabolome, as well as related functions, are of significance in differential responses of depressed rats to PX, which might be novel insights in uncovering the mechanisms of differences in efficacies of antidepressants. [Display omitted] • Paroxetine responsive and non-responsive rats differed significantly in metabolic profiles and microbiome. • The abundances of five intestinal flora and six fecal metabolites could distinguish PX-R and PX-N rats. • Integrative networks of behaviors-immunity-metabolomics-gut microbiota were constructed. [ABSTRACT FROM AUTHOR]

ObjectiveThe cytochrome P450 2D6 (CYP2D6) is an enzyme involved in the oxidative biotransformation of various widely used drugs, including paroxetine, a substrate and strong inhibitor of the enzyme. The aim is to report on a case of protracted intoxication with paroxetine after a single overdose in a genotype-predicted intermediate CYP2D6 metabolizer.ObservationA 49-year-old man was receiving chronic treatment for more than 6 years with paroxetine 60 mg/day for an indication of agoraphobia. The patient ingested fifty 20 mg tablets of paroxetine in a suicide attempt. The toxic plasma level, accompanied by delirium, persisted for approximately 1 month after the overdose. According to the genotype profile, the patient was evaluated as an intermediate metabolizer with reduced CYP2D6 enzyme activity.ConclusionAs a consequence of the suicide attempt with overdose and the chronic paroxetine treatment that preceded it, phenoconversion to a poor metabolizer with very low CYP2D6 enzyme activity is suggested as contributing to an extremely long intoxication accompanied by delirium. Prolonged monitoring over a standard 24 h of both physical symptoms and drug plasma levels, together with a genetic profile assessment and phenoconversion consideration, is recommended after a single overdose in patients chronically treated with paroxetine.

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Background: Impaired functional connectivity between the bilateral hemispheres may serve as the neural substrate for anxiety and depressive disorders, yet its role in comorbid generalized anxiety disorder (GAD) and depression, as well as the effect of treatment on this connectivity, remains unclear. We sought to examine functional connectivity between homotopic regions of the 2 hemispheres (voxelmirrored homotopic connectivity [VMHC]) among people with GAD with and without comorbid depression at baseline and after a 4-week paroxetine treatment. Methods: Drug-naive patients with GAD, with or without comorbid depression and healthy controls underwent functional magnetic resonance imaging and clinical assessments at baseline and after treatment. We compared VMHC and seed-based functional connectivity across the 3 groups. We performed correlation analysis and support vector regression (SVR) to examine the intrinsic relationships between VMHC and symptoms. Results: Both patient groups (n = 40 with GAD only, n = 58 with GAD and depression) showed decreased VMHC in the precuneus, posterior cingulate cortex and lingual gyrus compared with healthy controls (n = 54). Moreover, they showed decreased VMHC in different brain regions compared with healthy controls. However, we did not observe any significant differences between the 2 patient groups. Seeds from abnormal VMHC clusters in patient groups had decreased functional connectivity. Voxel-mirrored homotopic connectivity in the precuneus, posterior cingulate cortex and lingual gyrus was negatively correlated with cognitive impairment among patients with GAD only and among all patients. The SVR analysis based on abnormal VMHC showed significant positive correlations (p < 0.0001) between predicted and actual treatment responses. However, we did not observe significant differences in VMHC or functional connectivity after treatment. Limitations: A notable dropout rate and intergroup somatic symptom variations may have biased the results. Conclusion: Patients with GAD with or without comorbid depression exhibited shared and distinct abnormal VMHC patterns, which might be linked to their cognitive deficits. These patterns have the potential to serve as prognostic biomarkers for GAD. Clinical trial registration: ClinicalTrials.gov NCT03894085., Introduction Generalized anxiety disorder (GAD) is a prevalent anxiety disorder, with patients often experiencing a range of somatic discomforts. In addition, comorbid depression is frequently observed among people with GAD [...]

To identify which medications are mostly associated with ejaculatory disorders through a disproportionality analysis. The Food and Drug Administration Adverse Event Reporting System (FDA-FAERS) and the Eudra-Vigilance (EV) database were queried to identify medications more commonly associated to ejaculatory disorders from September 10, 2012 to June 1, 2023. Proportional Reported Ratios (PRRs) were computed for all the selected drugs. Overall, 7404 reports of ejaculatory disorders reports were identified, and of these, 6854 cases (92.6%) were attributed to ten specific medications. On FDA-FAERS and EV databases, Paroxetine and Tamsulosin were the main responsible of delayed ejaculation (103/448 events, 23.0%) and retrograde ejaculation (366/1033 events, 35.4%), respectively. Finasteride was mostly related to painful ejaculation and ejaculation failure, with 150 events (7.8%) and 735 events (38.4%) respectively. Within the group of high-risk medications, Sildenafil presented higher risk of ejaculatory disorders than Tadalafil (PRR = 5.85 (95%CI 5.09-6.78), P <.01). Ten drugs were recognized to display significant reporting levels of ejaculatory disorders. Among them, Finasteride and Sildenafil were responsible for the most reports in FDA-FAERS and in EV databases, respectively. Physicians should thoroughly counsel patients treated with these drugs about the risk of ejaculatory disorders. Further integration into clinical trials is needed to enhance the applicability and significance of these results. [ABSTRACT FROM AUTHOR]

Simple Summary: The objective of drug repurposing is to discover novel therapeutic uses for established pharmaceuticals. Paroxetine (PX), a commonly prescribed antidepressant, has demonstrated promising anticancer properties in experimental studies. Nevertheless, its precise role and mechanisms of action in triple-negative breast cancer (TNBC) remain incompletely elucidated. Our research findings propose that PX may impact TNBC by modulating critical molecular pathways, providing significant implications for enhancing chemosensitivity and identifying potential therapeutic synergies in clinical practice. These findings provide a basis for the creation of individualized treatment plans and the identification of the most effective therapeutic interventions to enhance treatment precision and effectiveness in patients with TNBC. The strategy of drug repurposing has gained traction in the field of cancer therapy as a means of discovering novel therapeutic uses for established pharmaceuticals. Paroxetine (PX), a selective serotonin reuptake inhibitor typically utilized in the treatment of depression, has demonstrated promise as an agent for combating cancer. Nevertheless, the specific functions and mechanisms by which PX operates in the context of triple-negative breast cancer (TNBC) remain ambiguous. This study aimed to examine the impact of PX on TNBC cells in vitro as both a standalone treatment and in conjunction with other pharmaceutical agents. Cell viability was measured using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, apoptosis was assessed through flow cytometry, and the effects on signaling pathways were analyzed using RNA sequencing and Western blot techniques. Furthermore, a subcutaneous tumor model was utilized to assess the in vivo efficacy of combination therapy on tumor growth. The results of our study suggest that PX may activate the Ca2+-dependent mitochondria-mediated intrinsic apoptosis pathway in TNBC by potentially influencing the PI3K/AKT/mTOR pathway as well as by inducing cytoprotective autophagy. Additionally, the combination of PX and chemotherapeutic agents demonstrated moderate inhibitory effects on 4T1 tumor growth in an in vivo model. These findings indicate that PX may exert its effects on TNBC through modulation of critical molecular pathways, offering important implications for improving chemosensitivity and identifying potential therapeutic combinations for clinical use. [ABSTRACT FROM AUTHOR]

Objective: Catheter-associated urinary tract infections make one of the leading nosocomial diseases worldwide. Most of the bacteria causing catheter-associated urinary tract infections form protective biofilms inside which the pathogens would be more resistant to antimicrobial agents, making the treatment more complicated resulting in severe sufferings of the patients with prolonged morbidity, increased hospital expenses and comparatively higher mortality. Treatment of infections caused by two of such pathogens - Enterococcus faecalis and Escherichia coli are challenging and the pharmaceutical world is trying to find alternative antimicrobial agents. Thus, the current investigation is a trial to repurpose paroxetine - an anti-depression drug to evaluate its antibacterial potentials against these pathogens. Material and methods The repurposing of paroxetine to evaluate its efficiency against Enterococcus faecalis and Escherichia coli was performed by agar diffusion method. Using microdilution protocols, the minimal inhibitory concentration was also calculated. To qualitatively analyse the anti-biofilm activity of the drug, paroxetine was coated on catheters and the activity was evaluated against the bacterial growth. Results: Paroxetine exhibited promising antibacterial activity and the minimum inhibitory concentrations were found to be 75 µg/ml and 37.5 µg/ml against Enterococcus faecalis and Escherichia coli respectively. The drug could also reduce the formation of biofilms by 72% in the case of Enterococcus faecalis and by 86% in case of Escherichia coli. Paroxetine also shown to possess potential anti-adhesive properties. Conclusion: The results suggest that the anti-depression drug paroxetine has antibacterial, anti-biofilm and anti-adhesive properties against two of the most prevalent bacteria involved in catheter-associated urinary tract infections. [ABSTRACT FROM AUTHOR]

Copyright of Firat Universitesi Sağlik Bilimleri Tip Dergisi is the property of Firat Universitesiu, Saglik Bilimleri Enstitusu and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of South China Fisheries Science is the property of South China Fisheries Science Editorial Department and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Introduction: Depression is strongly associated with Alzheimer's disease (AD). Antidepressants are commonly used in patients before and after their diagnosis of AD. To date, the relationship between antidepressants and AD remains unclear. Methods: In our study, we administered sertraline or paroxetine to wild type (WT) and APPswe/PSEN1dE9 (APP/PSEN1) transgenic mouse models for up to 12 months. We quantified the drug concentrations using LC-MS/MS analysis and measured serum serotonin level using an ELISA assay. Additionally, we evaluated the amyloid burdens through thioflavin-S and Congo red stainings, and recognition memory using the novel object recognition test. Results: Our findings revealed that mice treated with paroxetine exhibited a significantly higher level of weight gain compared to the control group and increased mortality in APP/PSEN1 mice. After 12 months of antidepressant treatment, the sertraline level was measured at 289.8 ng/g for cerebellum, while the paroxetine level was 792.9 ng/g for cerebellum. Sertraline significantly increased thioflavin-S and Congo red depositions, along with gliosis, in both isocortex and hippocampus of APP/PSEN1 mice compared to the control group. Both antidepressants also led to a decreased recognition index in APP/PSEN1 mice. Conclusion: These findings suggest a potential role of sertraline in AD pathogenesis, emphasizing the need to reassess the use of these antidepressants in patients with AD. [ABSTRACT FROM AUTHOR]

In human psychiatric medicine, the anxiolytic mirtazapine (MZ) is used as an adjunct to selective serotonin reuptake inhibitors (SSRIs) to reduce side effects and achieve faster behavioral control. To the best of our knowledge, the use of MZ as an adjunct agent to SSRIs has not been studied in canine psychiatric medicine. This retrospective study aimed to evaluate tolerance to and response to oral MZ (0.2-0.8 mg/kg once daily) as an adjunct to fluoxetine and paroxetine in client-owned dogs with fear-, anxiety-, or aggression-based disorders. Paroxetine use in canines has not been well studied; thus, results were compared to those of previous studies on fluoxetine as the sole anxiolytic. Dogs included in this study were treated with fluoxetine or paroxetine in combination with MZ, did not receive other daily medications (but could receive situational medications), and underwent at least 4 weeks of follow-up (n = 71). When using fluoxetine/MZ or paroxetine/MZ, 81.7% (n = 58) of owners reported Q4 improvement of their dog's condition. Compared with fluoxetine alone, dogs treated with paroxetine/MZ showed less inappetence and lethargy but more weight gain. Fluoxetine/MZ did not produce adverse effects (AEs) significantly different from those reported for fluoxetine alone. Discontinuation of MZ was required in 5.6% (n = 4) of patients due to excessive appetite increase, and 1.4% (n = 1) of patients discontinued both fluoxetine and MZ due to increased anxiety when starting either medication. No AEs were reported related to situational medication use, including trazodone (22.5%). This study provides evidence that the addition of oral MZ at a dose of 0.2-0.8 mg/kg once daily to paroxetine and fluoxetine is effective and well tolerated. The combination of paroxetine/MZ may reduce some AEs associated with fluoxetine. The combination of paroxetine/MZ may be a favorable alternative to fluoxetine, particularly in patients who have previously experienced undesirable AEs receiving fluoxetine. • Adding mirtazapine to paroxetine results in lower frequency of some adverse effects. • Use of paroxetine with mirtazapine (MZ) may be a favorable alternative to fluoxetine. • MZ with paroxetine or fluoxetine for behavioral treatment was well tolerated. • MZ as an adjunct may be beneficial for canine patients with behavioral disorders. [ABSTRACT FROM AUTHOR]

Summary: Background: Understanding the impact of CYP2D6 metabolism on paroxetine, a widely used antidepressant, is essential for precision dosing. Methods: We conducted an 8-week, multi-center, single-drug, 2-week wash period prospective cohort study in 921 Chinese Han patients with depressive or anxiety disorders (ChiCTR2000038462). We performed CYP2D6 genotyping (single nucleotide variant and copy number variant) to derive the CYP2D6 activity score and evaluated paroxetine treatment outcomes including steady-state concentration, treatment efficacy, and adverse reaction. CYP2D6 metabolizer status was categorized into poor metabolizers (PMs), intermediate metabolizers (IMs), extensive metabolizers (EMs), and ultrarapid metabolizers (UMs). The influence of CYP2D6 metabolic phenotype on paroxetine treatment outcomes was examined using multiple regression analysis and cross-ethnic meta-analysis. The therapeutic reference range of paroxetine was estimated by receiver operating characteristic (ROC) analyses. Findings: After adjusting for demographic factors, the steady-state concentrations of paroxetine in PMs, IMs, and UMs were 2.50, 1.12, and 0.39 times that of EMs, with PM and UM effects being statistically significant (multiple linear regression, P = 0.03 and P = 0.04). Sex and ethnicity influenced the comparison between IMs and EMs. Moreover, poor efficacy of paroxetine was associated with UM, and a higher risk of developing adverse reactions was associated with lower CYP2D6 activity score. Lastly, cross-ethnic meta-analysis suggested dose adjustments for PMs, IMs, EMs, and UMs in the East Asian population to be 35%, 40%, 143%, and 241% of the manufacturer's recommended dose, and 62%, 68%, 131%, and 159% in the non-East Asian population. Interpretation: Our findings advocate for precision dosing based on the CYP2D6 metabolic phenotype, with sex and ethnicity being crucial considerations in this approach. Funding: National Natural Science Foundation of China; Academy of Medical Sciences Research Unit.

Background: Pulmonary hypertension (PH) often leads to right ventricle (RV) failure, a significant cause of morbidity and mortality. Despite advancements in PH management, progression to RV maladaptation and subsequent failure remain a clinical challenge. This study explored the effect of paroxetine, a selective serotonin reuptake inhibitor (SSRI), on RV function in a rat model of PH, hypothesizing that it improves RV function by inhibiting G protein-coupled receptor kinase 2 (GRK2) and altering myofilament protein phosphorylation. Methods: The Su5416/hypoxia (SuHx) rat model was used to induce PH. Rats were treated with paroxetine and compared to vehicle-treated and control groups. Parameters measured included RV morphology, systolic and diastolic function, myofilament protein phosphorylation, GRK2 activity, and sympathetic nervous system (SNS) markers. Results: Paroxetine treatment significantly improved RV systolic function, evidenced by increased stroke volume, cardiac output, and ejection fraction, without significantly affecting RV hypertrophy, myosin heavy chain/titin isoform switching, or fibrosis. Enhanced phosphorylation of titin and myosin light chain-2 was observed, correlating positively with improved systolic function. Contrary to the hypothesis, improvements occurred independently of GRK2 inhibition or SNS modulation, suggesting an alternate mechanism, potentially involving antioxidant properties of paroxetine. Conclusion: Paroxetine improves RV systolic function in PH rats, likely through mechanisms beyond GRK2 inhibition, possibly related to its antioxidant effects. This highlights the potential of paroxetine in managing RV dysfunction in PH, warranting further investigation into its detailed mechanisms of action and clinical applicability.

Microneedles (MNs) prepared from polymeric materials are painless and minimally invasive, safe and efficient, but they hindered by low mechanical strength and single diverse drug release pattern. Due to the distinctive mechanical strength and dimensions of poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs), the integration of nano-technology with microneedles can effectively improve penetration and delivery efficiency through the stratum corneum. We herein designed a simple paroxetine (PAX)-loaded PLGA nanoparticles-integrated dissolving microneedles system (PAX-NPs-DMNs), aiming to improve the bioavailability of PAX through the synergistic permeation-enhancing effect of dissolving microneedles (DMNs) and NPs. PAX-NPs-DMNs had a complete tips molding rate (Neff) of (94.06 ± 2.16) %, a 15×15 quadrangular-conical microneedle array and an overall fracture force of 301.10 N, which were improved nearly 0.50 times compared with the blank microneedles (HA-DMNs) and PAX microneedles (PAX-DMNs). PAX-NPs-DMNs could extend the release duration of PAX from 1 h to 24 h and the cumulative permeability per unit area (Qn) was 47.66 times and 7.37 times higher than the PAX and the PAX-DMNs groups. PAX-NPs-DMNs could be rapidly dissolved within 10 min without hindering skin healing or causing adverse reactions. This study confirmed that PAX-NPs-DMNs can effectively improve the bioavailability of PAX and the mechanical strength of DMNs, which can easily penetrate the skin to provide sustained and painless delivery without causing adverse effects, thus offering a more convenient and effective method for central nervous diseases.